One Stone, Two Birds: N6-Methyladenosine RNA Modification in Leukemia Stem Cells and the Tumor Immune Microenvironment in Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia is the most common acute leukemia in adults, with accumulation of abundant blasts and impairment of hematogenic function. Despite great advances in diagnosis and therapy, the overall survival of patients with acute myeloid leukemia remains poor. Leukemia stem cells are the root cause of relapse and chemoresistance in acute myeloid leukemia. The tumor immune microenvironment is another trigger to induce recurrence and drug resistance. Understanding the underlying factors influencing leukemia stem cells and the tumor immune microenvironment is an urgent and unmet need. Intriguingly, N6-methyladenosine, the most widespread internal mRNA modification in eukaryotes, is found to regulate both leukemia stem cells and the tumor immune microenvironment. Methyltransferases and demethylases cooperatively make N6-methyladenosine modification reversible and dynamic. Increasing evidence demonstrates that N6-methyladenosine modification extensively participates in tumorigenesis and progression in various cancers, including acute myeloid leukemia. In this review, we summarize the current progress in studies on the functions of N6-methyladenosine modification in acute myeloid leukemia, especially in leukemia stem cells and the tumor immune microenvironment. We generalize the landscape of N6-methyladenosine modification in self-renewal of leukemia stem cells and immune microenvironment regulation, as well as in the initiation, growth, proliferation, differentiation, and apoptosis of leukemia cells. In addition, we further explore the clinical application of N6-methyladenosine modification in diagnosis, prognostic stratification, and effect evaluation. Considering the roles of N6-methyladenosine modification in leukemia stem cells and the tumor immune microenvironment, we propose targeting N6-methyladenosine regulators as one stone to kill two birds for acute myeloid leukemia treatment.

Keywords: N6-methyladenosine; RNA methylation; acute myeloid leukemia; leukemia stem cells; tumor immune microenvironment.

Figure 1

The functions of m⁶A RNA modification. m⁶A writers and erasers reversibly and dynamically regulate the m⁶A methylation modification. Readers can recognize and bind to the m⁶A methylation site to influence RNA fate, including nuclear exporting, splicing, stability, decay, and translation, as well as microRNA processing.

Figure 2

The outline of m⁶A modification in leukemia stem cells and the tumor immune microenvironment. Leukemia stem cells (LSCs) can maintain self-renewal and trigger leukemia cells proliferation. LSCs can escape from the surveillance and elimination of the immune system through various mechanisms. With the expression of TIM-3, LSCs secrete galectin-9 (Gal-9) to form TIM-3/Gal-9 autocrine loop. Meanwhile Gal-9 combines with TIM-3 expressed on T cells to inhibit T cells immunity. Furthermore, LSCs express PD-L1 to recognize and bind its receptor PD-1 on T cells to impede the killing of T cells. LSCs can also express LILRB4 and CD200 to suppress T cells activity. In addition, LSCs can express CD47 to combine with SIRPα on macrophages to escape from innate immune attacks and can suppress NKG2DL expression through PARP1 to avoid NK cells killing. m⁶A modification both participates in the regulation of LSCs and the TIME. METTL3, METTL14, FTO, ALKBH5, YTHDF2 and IGF2BP1 can both promote LSCs self-renewal and leukemia cells proliferation, while WTAP can only enhance leukemia cells proliferation. FTO regulates the expression of LILRB4 on LSCs to suppress T cells infiltration and cytokines secretion in an m⁶A-dependent way.